Cost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast Cancer

Key Points Question How cost-effective are ovarian and breast cancer risk reduction strategies among women with pathogenic variants in individual cancer susceptibility genes (ie, BRCA1, BRCA2, PALB2, RAD51C, RAD51D, and BRIP1)? Findings This economic evaluation using a decision-analytic Markov model with a simulated cohort of women aged 30 years found that undergoing both risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) was most cost-effective, maximizing cancers prevented for individuals carrying BRCA1 (RRM at age 30 years; RRSO at age 35 years), BRCA2 (RRM at age 35 years; RRSO at age 40 years), and PALB2 (RRM at age 40 years; RRSO at age 45 years) pathogenic variants, while RRSO was cost-effective at age 45 years for women with RAD51C, RAD51D, and BRIP1 pathogenic variants. Meaning These findings support personalizing risk-reducing surgery and guideline recommendations for individual cancer susceptibility gene–specific ovarian and breast cancer risk management.


eMethods 1. Detailed Probabilities Calculation
The breast cancer (BC) risk-reduction from risk-reducing mastectomy (RRM) was taken from the PROSE study for BRCA1/BRCA2 pathogenic variant (PV)-carriers, 6 which was 91% (95%CI: 62%-98%) and 95% (95%CI: 78%-99%) with or without risk-reducing salpingooophorectomy (RRSO), respectively.We assumed the same level of BC risk-reduction with RRM for PALB2 PV-carriers.The ovarian cancer (OC) risk-reduction from RRSO for BRCA1/BRCA2 PV-carriers was derived from BRCA1/BRCA2 related studies [7][8][9] (97%, 95%CI: 80%-99%), while bilateral salpingo-oophorectomy in average risk general population women in the Nurses' Health Study 10 also reported a similar level of OC riskreduction (97%, 95%CI: 86%-99%).Hence, we assume the OC risk-reduction for PALB2/RAD51C/RAD51D/BRIP1 PV-carriers to be similar (97%, 95%CI: 86%-99%) given lack of precise/specific data.There has been a level of uncertainty reported for BC riskreduction from RRSO, [64][65][66] and we used the most recent meta-analysis where BC riskreduction was only observed in BRCA2 PV-carriers (relative risk: 0.63, 95%CI: 0.41-0.97). 11sed on a similar proportion of oestrogen-receptor (ER) positive BC for BRCA2 and PALB2 PV-carriers, 48 we assumed the same BC risk-reduction from RRSO for PALB2 PV-carriers.80% of premenopausal women were assumed to receive hormone replacement therapy (HRT) after RRSO in the base case, given from the surgery age to the average menopause age (51 years). 12Excess risk of coronary heart disease (CHD) after premenopausal RRSO without HRT was incorporated using data from Nurses' Health Study. 10,13The excess risk of CHD is calculated by subtracting CHD incidence in women undergoing RRSO from that in women not having this surgery.The excess risk of CHD mortality was also taken from the Nurses' Health Study, 13 where CHD death was reported in 1 out of 33 premenopausal women undergoing RRSO but not taking HRT.
Medical prevention using tamoxifen or anastrozole for 5 years was based on the menopause status. 67We assume pre-menopausal women use tamoxifen and pos-menopausal women receive anastrozole.The risk-reduction effect was applied to ER-positive BC only, with hazard ratio of 0.66 (95%CI: 0.54-0.81)and 0.46 (95%CI: 0.33-0.65)from the extended long-term follow-up of the IBIS-I BC prevention trial 15 and IBIS-II trial 16 , respectively.The compliance of BC surveillance was assumed to be 100%.According to a UK study on enhanced BC surveillance, 21 women with ≥30% lifetime BC-risk undergo mammography and MRI surveillance, and the proportion of women diagnosed as ductal carcinoma in-situ (DCIS), stage 1 BC, stage 2 BC, and stage 3-4 BC was 20.00%, 54.36%, 24.62% and 1.03%, respectively.Women with 17-30% lifetime BC-risk undergo mammography surveillance, with 20.34%, 45.76%, 30.51%, and 3.39% of them diagnosed at DCIS, stage 1 BC, stage 2 BC, and stage 3-4 BC, respectively. 21False positive rates for MRI and mammography surveillance were included, which were 13.7% and 5.3%, respectively. 17Index or NHS cost inflation index were used to convert costs to the year of 2021. 39Where UK data was unavailable, we used consumer price index (CPI) 68 of original currency and purchasing power parities (PPP) 69 to convert data to 2021GBP.

Cost of risk-reducing strategies -RRM
The costs of RRM and reconstruction were derived from National Cost Collection for the NHS (financial year 2020/2021, the average unit cost of providing defined services to NHS patients in England). 32Around 90.6% reconstruction rate has been reported after RRM in the UK population. 33For RRM and reconstruction, the minor and major complication rate was reported to be 26.2% and 5.6%, respectively. 34The complication related costs were added to the costs of RRM (minor complication: £475, major complication: £4,331). 34

-RRSO
The RRSO costs were derived from National Cost Collection for the NHS, using the cost of an upper genital tract laparoscopic or endoscopic intermediate procedure. 32HRT costs were taken from published UK analyses, 35 which were obtained from the British National Formulary (BNF). 38Women were assumed to receive one follow-up DEXA scan for monitoring bone health, and calcium and vitamin-D3 for additional osteo-protection. 35The cost of DEXA scan was taken from National Cost Collection for the NHS, 32 and the osteoprotection cost was taken from Manchanda et al. 36 The HRT, DEXA scan, and osteoprotection costs were only applied to women who underwent RRSO before age 50 years.

CHD costs after premenopausal RRSO was derived from Heart & Circulatory Disease
Statistics 2022 from British Heart Foundation. 37The prevalence of CHD is around 3.2% 37 in the UK with the onset of CHD estimated at age 55 years. 13The annual cost of CHD was calculated by dividing the cost per capita by the population CHD prevalence.The fatal CHD cost was estimated based on a fatal myocardial infarction from National Cost Collection for the NHS. 32edical prevention Tamoxifen 20mg daily or anastrozole 1mg daily was given for 5 years for medical prevention, with uptake rate of 16.3% (obtained from a meta-analysis). 14The unit cost of tamoxifen and anastrozole was taken from BNF. 38 Cost of OC As the treatment for OC is standardised, we applied same OC treatment costs for BRCA1/BRCA2/PALB2/RAD51C/RAD51D/BRIP1 PV-carriers.The issue of poly (adenosine diphosphate-ribose) polymerase inhibitor (PARP-i) treatment for both BRCA-mutated or homologous-recombination-deficiency (HRD) positive advanced OC, is addressed in a scenario analysis.Our approach is conservative in the base-case given the additional significantly high costs of PARP-i.
-Diagnosis costs OC diagnosis includes pelvic examination, serum CA125 test, transvaginal ultrasound, CT scan, abdominal ultrasound with biopsy, histology and cytology assessment. 28The cost of pelvic examination was estimated using unit cost from the Personal Social Services Research Unit (PSSRU) and included the cost of GP's and nurse's time. 39Serum CA125 test cost was obtained from NICE OC guideline. 28The transvaginal ultrasound and CT scan costs were taken from National Cost Collection for the NHS, 32 while the costs of abdominal ultrasoundguided biopsy and histology and cytology assessment were obtained from interactive Costing Tool from National Institute for Health and Care Research (NIHR). 40

-Treatment costs
The OC surgery costs were estimated using reference costs for surgery and chemotherapy.
Surgery comprised NHS costs for a complex, open or laparoscopic, upper or lower genital tract procedure for malignancy. 32Patients were assumed to receive histological assessment of surgical specimen and clinical follow-up after surgery. 32,40For chemotherapy, patients would receive 6 cycles of carboplatin and paclitaxel.The chemotherapy costs include the appointment for planning chemotherapy, blood test for tumour marker, drug acquisition cost, and administration cost, derived from the National Cost Collection for the NHS, 32 the NIHR interactive Costing Tool, 40 the NICE OC guideline, 28 and BNF. 38During the treatment, women were assumed to receive two CT scans to monitor disease progression.Scenario analysis of using PARP-i (olaparib) for BRCA-mutated advanced OC, or olaparib plus bevacizumab for HRD-positive (non BRCA-mutated) advanced OC was conducted according to NICE recommendation. 70,71The list price of olaparib was £2,317.5/14-daypack from BNF, 38 with average treatment duration of 2 years. 18,19Bevacizumab was given for an average duration of 15 months, 19 with the list price of £205.55 for 100mg/4ml. 38

-Recurrence costs
The proportion of OC diagnosed at stage 3b-4 was 94.4% for women with increased OC-risk who did not receive surveillance, according to the UK Familial Ovarian Cancer Screening Study (Phase II). 27The recurrence rate of early and advanced OC was assumed to be 10% and 90%, respectively. 28The chemotherapy costs for OC recurrence were derived from Gilbert et al, 41 and 25% women with recurrence were assumed to receive secondary cytoreduction surgery based on the DESKTOP II trial. 4280% recurrence was assumed to occur in the first two years after active treatment. 28ollow up and terminal care costs Women were assumed to receive four consultant visits, four CA125 tests, and one CT scan each year for the first two years after active treatment. 28From the third year, women would receive two consultant visits, two CA125 tests, and one CT scan each year. 28The OC terminal care costs for the last 90 days prior to death was derived from Urban et al. 43 Cost of BC BC costs for different CSGs were adjusted for the differences in stage distribution, the proportion of being ER-positive, human epidermal growth factor receptor 2 (HER2)-positive, or lymph node positive.Based on the BRIDGES study, 48 31%, 75%, 73%, 50%, 65% BC were ER-positive, while 10%, 14%, 22%, 9%, 4% BC were HER2-positive for BRCA1, BRCA2, PALB2, RAD51C, RAD51D PV-carriers, respectively.The proportion of lymph node positive BC was 36%, 47%, 47%, 33%, 50% for BRCA1, BRCA2, PALB2, RAD51C, RAD51D PV-carriers, respectively. 4849% BC were assumed to be premenopausal. 35creening and diagnosis costs BRCA1/BRCA2/PALB2 PV-carriers were assumed to receive annual MRI from age 30-49 years and annual mammography from age 40-69 years (High-risk BC surveillance), while RAD51C/RAD51D PV-carriers were assumed to receive annual mammography from age 40-59 years, and then routine triennial mammography as per NHS BC screening programme from age 60 years (Moderate-risk BC surveillance). 67BC diagnosis was made by the combination of clinical examination, mammography, and biopsy.The costs of clinical breast examination, mammography, MRI scan, ultrasound guided core needle biopsy were derived from National Cost Collection for the NHS 32 and NICE familial BC costing report 44 .
-Pre-treatment axilla ultrasound costs Pretreatment ultrasound evaluation of the axilla should be offered to all patients being investigated for early invasive cancer. 51Ultrasound-guided needle biopsy should be offered if morphologically abnormal lymph nodes are identified (around 33% of women with early invasive BC). 26,51The commissioning cost of pre-treatment ultrasound evaluation of the breast and axilla was the same as that of the breast only. 26Therefore, only the cost of ultrasound-guided needle sampling was included for the costing model, taken from National Cost Collection for the NHS. 32entinel lymph node biopsy (SLNB) costs SLNB is the preferred technique for staging the axilla for early invasive BC and no evidence of lymph node involvement on ultrasound or a negative ultrasound-guided needle biopsy. 51% , 68%, and 38% of stage 1, stage 2, and stage 3-4 BC were assumed to undergo this procedure, based on a BC costing study in England. 45The SLNB cost was obtained from National Cost Collection for the NHS, 32 including the sentinel lymph node scan and unilateral intermediate breast procedure.
-Axillary lymph node dissection (ALND) costs ALND should be offered to women with positive axillary lymph node BC. 51 Cost of ALND is assumed to be 25% of the cost of breast surgery according to NICE BC guideline development group recommendation. 25reast surgery costs Breast surgery include breast conserving surgery and mastectomy.All women with noninvasive BC were assumed to undergo breast conserving surgery.78%, 52%, and 33% of stage 1, stage 2, and stage 3-4 BC would undergo breast conserving surgery, while 16%, 35%, and 67% would undergo mastectomy (with/without reconstruction).45 23.3% reconstruction rate following mastectomy was reported for UK BC patients.46 The minor and major complication rate was reported to be 19.5% and 2.0% following mastectomy alone, and 24.5% and 4.1% following mastectomy and reconstruction.47 The breast surgery costs were derived from National Cost Collection for the NHS, 32 and the minor or major complications costs from published literature.34 -Chemotherapy and radiotherapy costs Adjuvant therapy is offered to women with invasive BC who are not at low-risk as per NICE BC guidelines.49,51 Chemotherapy was based on polychemotherapy, including costs of planning, administration, first-line, second-line, and third-line (where applicable) therapy and related toxicity management, derived from NICE advanced BC guideline.49 9%, 24%, and 44% of stage 1, stage 2, and stage 3-4 BC were assumed to receive chemotherapy.45 Radiotherapy is offered at a treatment centre 5 days a week for 3 weeks, using external beam radiotherapy giving 40 Gy in 15 fractions.51 70%, 61%, and 83% of stage 1, stage 2, and stage 3-4 BC would receive radiotherapy.45 Costs of planning and radiotherapy were taken from National Cost Collection for the NHS.32 -Endocrine therapy costs Women with ER-positive BC would receive endocrine therapy, with tamoxifen 20mg daily (premenopausal) or anastrozole 1mg daily (postmenopausal) according to NICE BC guidelines.49,51 The duration of endocrine therapy was assumed to be 5 years. Th unit cost of tamoxifen and anastrozole was obtained from BNF, 38 and the ER test cost (for all invasive cancers) was taken from a local NHS trust.35 -Biological therapy costs Women with HER2-positive invasive BC are eligible for adjuvant trastuzumab therapy, given at 3-week intervals for 1 year or until recurrence.51 10% of the eligible patients were assumed to be intolerant of trastuzumab because of the risk of adverse events. 26For patients suitable for trastuzumab treatment, 80% would receive the therapy.26 It was assumed that 80% patients taking trastuzumab would experience disease progression outside the central nervous system, and 50% would continue taking trastuzumab.26 The HER-2 test cost (for all invasive cancers) was taken from a local NHS trust.35 The trastuzumab costs including administration and cardiac monitoring were £19,770 per patient, taken from NICE BC costing report.26 -PARP-i costs Olaparib is recently recommended as an option for the adjuvant treatment of BRCA-mutated HER2-negative high-risk early BC that has been treated with neoadjuvant or adjuvant chemotherapy by NICE.72 Olaparib treatment was only included in a scenario analysis for BRCA1/BRCA2 PV-carriers.The list price of olaparib was taken from BNF, 38 and the duration of treatment was assumed to be 1 year.20

-Bisphosphonate costs
Bisphosphonates should be considered for patients newly diagnosed with bone metastases to prevent skeletal-related events and reduce pain. 4974% advanced BC patients were assumed to develop bone metastases, and 87% of those with bone metastases were offered bisphosphonates. 26,50,73The commonly used bisphosphonates included oral sodium clodronate, oral ibandronic acid, intravenous zoledronic acid, and intravenous pamidronate disodium, 26,51 and the proportion of patients receiving these drugs was 20%, 30%, 25% and 25%, respectively. 26The annual drug costs (including administration costs) were £2,348, £3,333, £4206, and £3,734, respectively, taken from NICE BC costing report. 26The bisphosphonate treatment duration was assumed to be 2 years, which was based on the life expectancy of advanced BC with bone metastases. 52ecurrence costs For non-invasive BC, there was a 25% risk of local recurrence over 10 years and half of these recurrences would be invasive cancer. 25For early and locally advanced BC, the locoregional recurrence rate was 15.9% for node-positive disease, 22 and 11.0% for node-negative disease. 23Based on the proportion of lymph node positive BC, 48 the weighted locoregional recurrence rate was 12.76%, 13.30%, 13.30%, 12.62%, and 13.45% for BRCA1, BRCA2, PALB2, RAD51C, and RAD51D PV-carriers, respectively.The distant recurrence rate was 35% for early and locally advanced BC. 26 The recurrence rate for advanced BC was reported to be 66.3%, derived from the 33.7% relapse-free 5-year survival. 24ollow-up and terminal care costs After active BC treatment, patients were assumed to receive clinical follow-up every four months in the first two years, every six months from the third to the fifth year, and every year from the sixth to the tenth year.They were also offered annual mammography surveillance for ten years.The cost of clinical follow-up was obtained from National Cost Collection for the NHS. 32The terminal care costs for BC in the last year prior to death were derived from a UK study by Round et al. 53 eMethods 3. Survival of Ovarian or Breast Cancer and Impact of Risk-Reducing Surgery As no statistically significant difference was reported in the long-term survival between CSGassociated and sporadic OC, [74][75][76][77] we used the 10-year OC survival of 35.3% (95%CI: 34.0%-36.7%) in general population from Cancer Research UK. 31 BC survival under mammography and MRI surveillance was taken from a UK study for 14,311 women by Evans et al, 21 and the 10-year survival was 91.2% (95%CI: 77.8%-96.6%)for BRCA1 and 93.7% (95%CI: 81.6%-97.9%)for BRCA2 PV-carriers, respectively.The BC survival for PALB2/RAD51C/RAD51D PV-carriers was derived from the FH01 study on mammographic surveillance for moderate BC-risk UK women, where 10-year survival of 84.0% (95%CI: 81.0%-87.0%)was reported. 30Women were considered long-term survivors if they were alive without evidence of recurrence 10 years after cancer diagnosis.Long-term cancer survivors were assumed to have the same probability of death as the general population.
The impact of risk-reducing surgery on cancer survival was included in our model.The BC survival after RRSO for BRCA1/BRCA2 PV-carriers was taken from a recent meta-analysis. 11sed on BC pathological features, 48 we applied the same impact on BC survival from RRSO for PALB2 PV-carriers as that for BRCA2 PV-carriers, and for RAD51C/RAD51D PV-carriers as that for BRCA1 PV-carriers.The OC survival after RRSO for BRCA1/BRCA2 PV-carriers was obtained from a meta-analysis conducted for the NICE guideline, which was also assumed for PALB2/RAD51C/RAD51D/BRIP1 PV-carriers.A reduction in overall mortality after RRSO was reported for BRCA1/BRCA2 PV-carreirs. 78,79Hence, we applied reduced overall mortality after RRSO for BRCA1/BRCA2 PV-carriers who did not develop cancer, and we also assumed the same impact for other CSG-carriers associated with an increased risk of OC in the base-case as CSG-specific data are lacking.This issue was further explored in a scenario analysis with no impact on overall mortality in other (non-BRCA) OC CSGcarriers.[82][83] Additionally no added risk of overall mortality has also been reported. 84r the scenario analysis of using PARP-i (olaparib), the hazard ratio for overall survival was 0.68 (98.5% CI: 0.47-0.97)for BRCA-mutated HER2-negative early BC, taken from the prespecified second interim analysis of the OlympiA phase III trial. 20Improvement in overall survival after olaparib for BRCA-mutated advanced OC (hazard ratio: 0.55, 95% CI: 0.40-0.76)was taken from the SOLO1/GOG 3004 Trial. 18Overall survival benefit was recently reported for primary maintenance treatment with olaparib plus bevacizumab for HRDpositive advanced OC (hazard ratio: 0.62, 95%CI: 0.45-0.85)from the prespecified final overall survival analysis for the PAOLA-1/ENGOT-ov25 trial. 19For our analysis we used the overall survival of olaparib plus bevacizumab treatment for HRD-positive "not BRCAmutated" advanced OC (hazard ratio: 0.71, 95%CI: 0.45-1.13)for PALB2/RAD51C/RAD51D/PALB2 PV-carriers. 19Methods 4. Detailed Utility Score Calculations Quality-adjusted life-years (QALYs) are the recommended generic measure of health benefit by NICE, which reflects both mortality and health-related quality-of-life effects. 85It equals time spent in a specific health state multiplied by the corresponding utility score.Utility score is an indicator of individual preference for a specific health state, where '1' implies perfect health and '0' implies death.Utility score is used for quality-of-life adjustment for different health states included in the model.Utility scores of prevention and surveillance strategies were derived from time trade-off (TTO) surveys among women with or without BRCA1/BRCA2 PV. 55,56 Utility scores of RRM, RRSO, medical prevention, mammography surveillance, and MRI surveillance were 0.88, 0.95, and 0.95, 0.97, and 0.96 for BRCA1/BRCA2 PV-carriers, respectively.We also applied these utility scores to non-BRCA PV-carriers due to lack of data.The disutility of RRSO and RRM were applied during the year of surgery, and disutility of CHD after premenopausal RRSO was included, which was taken from an EQ-5D-3L survey by Nyman et al. 57 The disutility of BC surveillance attendance was applied for the year of screening, and a disutility of 0.105 from a visual analogue scale (VAS) survey was further assigned in case of a false positive result for one year. 58,59ility scores of OC were derived from a survey of OC patients and females of general public. 60Utilities were reported by both TTO and VAS in this study, and we chose the estimates using TTO as visual scales comparing health state preferences were subject to inherent biases and usually less accurate. 86Utility scores of early, advanced, recurrent, remittent, and terminal OC were 0.600, 0.490, 0.400, 0.600, and 0.160, respectively. 60BC utility scores were derived from a NIHR health technology assessment conducted by Robertson et al, 61 where utility scores of different BC stages were taken from a systematic review and adjusted for the decrement from chemotherapy.Utility scores of DCIS, stage 1, stage 2, and stage 3-4 BC were 0.712, 0.597, 0.527, and 0.497, respectively. 61Utility scores of recurrent and remittent BC were derived from the pooling of utilities from studies using health state descriptions or standard gamble by Cooper et al, 62 which was 0.450 and 0.810, respectively.Utility score of terminal BC (0.160) was derived from a literature review on utility scores of BC related health states. 63l health state utility scores were age-adjusted using multiplicative method, 87 which combined age-specific utility scores in the 'healthy' state with utilities in all other health states.The population norms of utility scores were taken from the Health Survey for England, where EQ-5D-3L questionnaire was used. 54

eMethods 2 .
Detailed Cost Calculations UK costs data were used wherever possible, and the Hospital & Community Health Services